Xiaoxiao Liu,1,* Yushuang Luo,2,* Yiyu Huang,1 Mengfei Li,1 Ming Guo,1 Zheyi Dong,1 Jie Wu,1 Guangyan Cai,1 Hanyu Zhu,1 Kaifa Wang,2 Xiangmei Chen,1 Ping Li,1 Qinggang Li1 

1Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of China; 2Department of Mathematics and Statistics, Southwest University, Chongqing, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Qinggang Li; Ping Li, Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Beijing, People’s Republic of China, Email lqgbj301@126.com; liping.8@163.com

Rationale: The diagnostic value of endothelial-associated biomarkers in IgAN and their ability to differentiate it from other kidney diseases have not yet been clarified.
Objective: This study aimed to investigate the diagnostic value of endothelial-associated biomarkers in IgAN patients.
Methods and Results: This is a cross-sectional study involving 96 participants, with IgAN, LN, MN, and healthy subjects recruited in a 1:1:1:1 ratio. Seventy-five percent of the sample was used for developing a classification model, and the remaining 25% was used for constructing a validation cohort. Plasma levels of 12 endothelial-associated biomarkers were detected using multiplex immunoassay technology. Among all the biomarkers evaluated, VLA-4 and VEGFD were prioritized for distinguishing IgAN from other groups (p< 0.001), with 85% classification accuracy. These two biomarkers also showed significant correlation with eGFR (VLA-4: r = - 0.291, P = 0.021; VEGFD: r = - 0.271, P = 0.031) and Gd-IgA1 (VLA-4: r = 0.403, P = 0.003; VEGFD: r = 0.412, P = 0.002). These two biomarkers also showed superior diagnostic efficacy (AUC=0.952 and 0.945) compared to Gd-IgA1 (AUC=0.736). Subgroup analysis of IgAN patients revealed clinically relevant effect sizes for the IgA and IgA/C3 ratios between high- and low-VLA-4 and VEGFD groups, with Hedges’ g values of 0.962 and 0.819, respectively. The diagnostic efficacy of VLA-4 and VEGFD levels in IgAN was further validated in an independent cohort comprising 24 participants.
Conclusion: VLA-4 and VEGFD emerge as robust, non-invasive biomarkers for IgAN diagnosis and may play significant roles in the pathogenesis of IgAN.
Plain Language Summary: We investigated the diagnostic value of endothelial-associated biomarkers in Immunoglobulin A nephropathy patients. We identified two endothelial-associated biomarkers, VLA-4 and VEGFD, that could be used as biomarkers to distinguish IgAN patients from individuals with other types of glomerulonephritis and healthy subjects. We consider VLA-4 and VEGFD may play a significant role in mediating vascular endothelial damage and can serve as potential diagnostic biomarkers in patients with IgAN.

Keywords: IgA nephropathy, vascular injury, endothelial-associated biomarkers, machine learning